A Homozygous CARD9 Mutation in a Family with Susceptibility to Fungal Infections

By E. Glocker, A. Hennigs, M. Nabavi, Alejandro A. Schäffer, C. Woellner, U. Salzer, D. Pfeifer, H. Veelken, K. Warnatz, F. Tahami and 9 more. New England Journal of Medicine, 2009

787 citations recorded by the source corpus.

BACKGROUND Chronic mucocutaneous candidiasis may be manifested as a primary immunodeficiency characterized by persistent or recurrent infections of the mucosa or the skin with candida species. Most cases are sporadic, but both autosomal dominant inheritance and autosomal recessive inheritance have been described. METHODS We performed genetic studies in 36 members of a large, consanguineous five-generation family, in which 4 members had recurrent fungal infections and an additional 3 members died during adolescence, 2 after invasive infection of the brain with candida species. All 36 family members were enrolled in the study, and 22 had blood samples taken for DNA analysis. Homozygosity mapping was used to locate the mutated gene. In the 4 affected family members (patients) and the 18 unaffected members we sequenced CARD9, the gene encoding the caspase recruitment domain-containing protein 9, carried out T-cell phenotyping, and performed functional studies, with the use of either leukocytes from the patients or a reconstituted murine model of the genetic defect. RESULTS We found linkage (lod score, 3.6) to a genomic interval on chromosome 9q, including CARD9. All four patients had a homozygous point mutation in CARD9, resulting in a premature termination codon (Q295X). Healthy family members had wild-type expression of the CARD9 protein; the four patients lacked wild-type expression, which was associated with low numbers of Th17 cells (helper T cells producing interleukin-17). Functional studies based on genetic reconstitution of myeloid cells from Card9−/− mice showed that the Q295X mutation impairs innate signaling from the antifungal pattern-recognition receptor dectin-1. CONCLUSIONS An autosomal recessive form of susceptibility to chronic mucocutaneous candidiasis is associated with homozygous mutations in CARD9.

Subfields: Epidemiology, Immunology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/1ca66be53c4301392f14743350c75cdecbe44b8d

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Citations in the corpus

The SYK tyrosine kinase: a crucial player in diverse biological functions (2010, background): “Consistent with an essential role of the CLEC7A–SYK–CARD9 axis for antifungal host defence, CARD9-deficient mice and humans are highly susceptible to fungal infection”
30 years of NF-κB: a blossoming of relevance to human pathobiology (2017, positive): “CARD9 deficient patients also have decreased Th17 T cells, which are crucial for controlling mucosal, but not systemic candidiasis (Glocker et al., 2009).”
Neutrophils: Between Host Defence, Immune Modulation, and Tissue Injury (2015, background): “Mutations in CARD9, a protein essential for the sensing of fungi, lead to Candida infections [167], which was recently linked to impaired neutrophil killing [168].”
HIV and Tuberculosis: a Deadly Human Syndemic (2011, background): “Th17 cells recognize bacterial and fungal (and, less commonly, viral) antigens, secrete IL-17 and IL-22, and contribute to immunity to yeasts, extracellular bacteria (114, 166, 190), and, possibly, M.”
Dectin-2 recognition of alpha-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans. (2010, background): “Also, it was reported that patients with a homozygous CARD9 mutation become susceptible to fungal infection (Glocker et al., 2009).”
Candida albicans morphogenesis and host defence: discriminating invasion from colonization (2011, positive): “, together with the discovery that host mutations in dectin 1 or CARD9 lead to primary immunodeficiencies associated with fungal infection”
Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis (2011, background): “The proportion of IL-17A–producing T cells was also found to be low in a family with AR CARD9 deficiency, dermatophytosis, invasive candidiasis, and CMC (Glocker et al., 2009).”
Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome (2012, background): “Deficiency in either dectin-1 or CARD9 in human results in hypersusceptibility to mucocutaneous fungal infection”
Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. (2011, background): “albicans infection in vivo is also shown in humans and mice (Gross et al., 2006; Glocker et al., 2009).”